Early alcoholic liver disease is characterized by an increase lipid accumulation, pro-inflammatory cytokine production and hepatocellular damage, or steatohepatitis. The transition from steatohepatitis to fibrosis involves the activation of hepatic stellate cells and production of collagen, but the mechanisms regulating this transition represent critical gaps in our understanding of fibrogenesis. Clearly, cytokines such as TNF1 and TGF2 play critical roles, and emerging evidence suggests that Th2 cytokines, though not sufficient to produce a fibrotic response, are necessary. The relationship between lipid accumulation and cytokine production, however, is a consistent theme in nearly every stage of ethanol induced liver injury. There have been a number of reports linking a number of different fatty acid binding proteins (FABP), lipid transporters involved in lipid signaling and metabolism, to the regulation of cytokine expression. Specifically, the L-FABP isoform, which is suppressed after chronic ethanol exposure, has been shown to regulate hepatic IL12 expression, an anti-Th2 cytokine. Moreover, the FABP5 isoform is linked to IL17 regulation, a cytokine which was recently shown to be involved alcoholic liver disease. Thus, FABP represents an important mechanistic link between the accumulation of lipid in liver and cytokine production. The experiments outlined in this proposal will test the central hypothesis that lipid binding proteins FABP, L-FABP and mal1 (FABP5) regulate hepatic Th2 cytokine expression in response to ethanol. Here, we'll use mice lacking the liver isoform of FABP (L-FABP-/-) and the adipose/macrophage-specific FABP (FABP5-/-) to specifically address this question. We will also employ models of acute ethanol exposure and chronic Leiber-DeCarli liquid/ ethanol diet to address the role of FABPs in cytokine regulation as well as liver pathogenesis. Our pilot data suggest indeed ethanol sensitizes mice exacerbated a hepatic Th2 response. Thus we will characterize the hepatic Th1/Th2 response T cell dependent hepatitis in mice exposed to ethanol. Our pilot data also suggest that FABP expression is altered in response to ethanol. In the subsequent aims, the role of FABPs in Th1/Th2 cytokine regulation will be determined. Lastly, the role of L-FABP-/- and FABP5-/- in chronic ethanol induced liver injury, in particular ethanol induced liver fibrosis, will be assessed. The rationale is that since that fat metabolism and the transition to liver fibrosis are integrally connected, we hypothesize FABP null mice are more susceptible to fibrosis caused by chronic ethanol. In conclusion, we expect the results of these experiments to represent important mechanistic links between the mechanisms of lipid metabolism and hepatic fibrogenesis. PUBLIC HEALTH RELEVANCE: The accumulation of lipid in the liver is an early and critically important pathological characteristic of several liver diseases including both alcoholic liver disease and non-alcoholic steatohepatitis. Liver fibrosis is a progressive stage of chronic liver disease where excess collagen and extracellular matrix is produced. The mechanisms regulating the transition from steatohepatitis to fibrosis are unknown. Here, we will investigate the role of T lymphocytes and the production of T cell derived cytokines in fibrogenesis.